Critical Review. HIV Receptors and Cellular Tropism

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1 IUBMB Life, 53: , 2002 Copyright c 2002 IUBMB /02 $ DOI: / Critical Review HIV Receptors and Cellular Tropism Robin A. Weiss Department of Immunology and Molecular Pathology, University College London, London W1T 4JF, United Kingdom Summary Viruses use specific cell surface receptors to bind to and subsequently gain entry into their host cells. Some retroviruses such as HIV-1 and HIV-2 utilize one receptor for high-affinity binding (CD4), and a separate coreceptor to mediate fusion of the viral envelope with the cell membrane (CCR5 or CXCR4). The identification of these receptors explains the cellular tropism of HIV, and hence its pathogenesis leading to immune deficiency (T-helper cell depletion), the wasting syndrome (macrophage infection), and dementia (microglia infection). HIV can infect cells by membrane fusion at the cell surface and by receptor-mediated endocytosis. Knowledge of the HIV receptors has led to practical developments such as inhibitory drugs, reasons for genetic resistance to infection, and should inform the judicious choice of candidate vaccines. IUBMB Life, 53: , 2002 Keywords AIDS; HIV; receptor; tropism. INTRODUCTION The human immunodeficiency viruses (HIV-1, HIV-2) have only recently colonized human populations, having crossed species from the chimpanzee and sooty mangabey hosts respectively (1). Like other lentiviruses of primates, HIV-1 and HIV-2 utilize CD4 and chemokine receptors as a means to infection. As intracellular parasites, viruses have evolved a variety of mechanisms to gain entry into the host cell. The molecules on the cell membrane to which viruses attach and interact to mediate entry are called receptors. Such receptors have natural functions at the cell surface and have been hijacked by the virus to serve as entry gates into the cell. The recognition epitopes on receptors may be carbohydrates borne on glycoproteins and glycolipids, like the sialic acid residues used by influenza viruses, or they may be an integral part of the conformation of cell surface proteins, as is the Received 25 March 2002; accepted 30 March Address correspondence to Robin Weiss, Wohl Virion Centre, Windeyer Institute of Medical Sciences, 46 Cleveland Street, London, W1T 4JF, UK. Fax: +44(0) r.weiss@ucl.ac.uk case for the known HIV receptors. Fig. 1 depicts HIV receptors in schematic form. The CD4 receptor for HIV is a member of the immunoglobulin superfamily, whereas the chemokine coreceptors belong to the 7-transmembrane G-protein large family of coupled receptors. Soon after the discovery that CD4 is the HIV receptor (2, 3) we found that CD4 is necessary but not sufficient for HIV entry into cells. For example, mouse cells expressing human CD4 were permissive for high-affinity binding of HIV-1, but not for fusion or entry (4) (Fig. 2). Although all strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) recognized CD4 (5), different isolates appeared to require distinct secondary receptors in order to undergo fusion and entry (6). After many years of futile search, the second receptors or coreceptors were eventually identified as chemokine receptors, initially by Berger and colleagues (7, 8). Many groups soon showed that several kinds of chemokine receptor could serve as coreceptors to CD4 for HIV entry (9). However, in vivo only two coreceptors have thus far been shown to be utilized by HIV, namely CCR5 and CXCR4. Primary isolates of HIV infect macrophages and peripheral blood mononuclear cells (PBMC) of the T-helper lymphocyte lineage. These strains of HIV interact with the CCR5 receptor, which naturally binds the chemokines RANTES, MIP-1α, and MIP-1β. Late in the course of HIV infection progressing to AIDS, HIV variants frequently appear that become readily adapted to propagate in immortalized CD4-positive T-cell lines. These HIV substrains are syncytium inducing (SI), and utilize the CXCR4 chemokine receptor as a coreceptor with CD4. The natural ligand for CXCR4 is stromal-derived factor (SDF-1). Some primary isolates are dual-tropic and can recognize both CCR5 and CXCR4. Interestingly, subtype C HIV-1 seldom generates SI variants (10, 11), although they have been observed in isolates from South African patients. Retrovirus Attachment, Receptor Interaction, and Entry The first step in virus infection is adsorption to the cell surface. Even before interaction with the specific, high-affinity 201

2 202 WEISS Figure 1. Schematic diagram of cell surface molecules that serve as receptors for HIV. receptor occurs, adsorption involves extracellular molecules such as glyco-amino-glycans. Heparan has been shown to act as an initial adsorption for HIV onto adherent cell lines (12) although it is not strongly expressed on T-lymphocytes. Heparan adsorption may not require viral glycoproteins. Using direct visualization of virus particles, similar levels of adsorption by MLV to adherent cell lines were observed for virions lacking envelope glycoproteins (13). Binding to the specific virus receptor induces conformational changes in the SU glycoprotein to expose a hydrophobic domain in the TM protein that in turn effects membrane fusion. This series of events can be complex, as exemplified with HIV. The gp120-cd4 interaction induces conformational changes in both molecules, allowing access to the coreceptors, which in turn expose the fusion domain in gp41. These interconnections occur in the context of trimeric gp120/gp41 envelope spikes interacting with more than one CD4 molecule and coreceptor (9). The epitopes on receptors that are recognized by the retrovirus envelope glycoproteins have been mapped in several cases. Fine structure data at the crystallographic level have been achieved thus far only for HIV gp120 with CD4 (14). The cellular tropism of HIV is largely determined by the cell surface receptors it uses for binding and entry. HIV infects and eventually destroys T-helper lymphocytes but not T-killer lymphocytes, because the T-helper cells express CD4 whereas the cytotoxic T-cells express CD8. Macrophages express lower levels of CD4 and are also susceptible to HIV infection. Other receptors may play a role in HIV adsorption and infection in special circumstances. Certain kinds of dendritic cells (DC), including the Langerhans cells of the genital mucosa, express DC- SIGN, a C-type lectin recognized by HIV gp120. It is thought that this receptor may not permit membrane fusion, but can deliver virus to T-helper cells when taken up by DC cells that migrate to the lymph node (15). Another route to adsorption and entry is via Fc and complement receptors when HIV is coated with antibody. Because macrophages express FcR and CR, these Figure 2. CD4 antigen is necessary but not sufficient for HIV-1 infection. When a CD4 cdna expression construct was introduced into human HeLa cells, they became sensitive to binding of HIV-1 gp120, syncytium induction, infection by vesicular stomatitis pseudotypes bearing HIV envelope, and to HIV-1 itself. But mouse NIH-3T3 cells expressing human CD4, while binding gp120, were resistant to each other measure of infection (4). These results indicated that a second receptor is required for entry after the binding of HIV-1.

3 CELL SURFACE RECEPTORS 203 Figure 3. Electron micrographs showing HIV-1 infection by fusion at the cell surface membrane (A D) and by receptor mediated endocytosis (E H). Reproduced with permission from Weiss (27) with micrographs kindly provided by H. Gelderblom.

4 204 WEISS receptors may play a role in antibody-enhancement of HIV infection (16). There are two major pathways by which viruses penetrate cell membranes to gain access to the cytoplasm and to commence replication. One is direct fusion of the plasma membrane at the cell surface. This route is typical of paramyxoviruses such as measles virus. The second route is via receptor-mediated endocytosis, typical of influenza virus. These viruses are dependent on the low ph of endocytic vesicles for conformational changes in their envelope glycoproteins that expose hydrophobic membrane fusion domains. Fusion can be inhibited by raising endosomal ph with agents such as monensin, NH 4 Cl, and chloroquine. Studies with HIV-1 and HIV-2 indicate that they do not require acidic endosomes for infection (17, 18). Although most HIV strains are ph-independent for infection, they may still be able to enter via endosomes. Fig. 3 illustrates HIV-1 particles fusing at the cell surface and in the endosome, and either pathway can result in infection. The route of entry, however, will determine which region of the host cell s cytoplasm the virus reaches. This can influence restrictions on virus replication that occur after envelope fusion but before migration to the nucleus. For instance, a strain of HIV-2 that is restricted for infection of HeLa-CD4 cells could replicate efficiently after delivery to a different cellular compartment by pseudotyping with VSV G protein (19). Receptors in Prevention and Therapy The expression of retroviral receptors can have a profound effect on infection. Absence of receptors leads to resistance to infection and low levels of receptor expression can delay progression to disease (20). A common genetic polymorphism in the Caucasian population is a 32-base-pair deletion in the CCR5 gene preventing surface expression of the receptor. Homozygotes lacking CCR5 are generally resistant to HIV infection and they are overrepresented among HIV-exposed, yet uninfected, people (9, 20). The few homozygotes who have become HIV positive have been infected with CXCR4-using strains of HIV. HIV infection can also be prevented by competitively blocking receptors so that the virus cannot gain access to them. A number of agents have been developed that block CCR5 or CXCR4 (21, 22). Soluble forms of receptor can block infection by neutralizing the virus either by competitively inhibiting attachment to the cell-bound receptors or by prematurely triggering the viral envelope leading to inactivation. This was first shown with recombinant soluble CD4 (23). T-cell line-adapted strains of HIV-1 are highly sensitive to soluble CD4 (24), but unfortunately primary strains are semiresistant (25). The difference was explained by finding that with CXCR4-using virus, soluble CD4 irreversibly uncouples gp120 from the TM protein, gp41 thus inactivating the virus (26). Thus, much knowledge has been gained by identifying cell surface receptors for retroviruses. This information has helped our understanding of mechanisms of virus entry into cells and, potentially, how to block infection. Because receptor expression correlates with the cellular tropism of the virus, it has helped to explain aspects of retroviral pathogenesis. Receptors could be relevant to vaccine design in the future. CCR5 is required for the vast majority of HIV particles that transmit from one individual to another. The conformational epitopes on gp120 that interact specifically with CD4 and CCR5 must be conserved to maintain infectivity. Thus, these epitopes represent suitable targets for vaccine design. ACKNOWLEDGEMENT The author s research is funded by the Medical Research Council and by Cancer Research United Kingdom. REFERENCES 1. Weiss, R. A., and Wrangham, R. W. (1999) The origin of HIV-1: from Pan to pandemic. Nature 397, Dalgleish, A. G., Beverley, P. C., Clapham, P. R., Crawford, D. H., Greaves, M. F., and Weiss, R. A. (1984) The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312, Klatzmann, D., Champagne, E., Chamaret, S., Gruest, J., Guetard, D., Hercend, T., Gluckman, J. C., and Montagnier, L. (1984) T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature 312, Maddon, P. J., Dalgleish, A. G., McDougal, J. S., Clapham, P. R., Weiss, R. A., and Axel, R. (1986) The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47, Sattentau, Q. J., Clapham, P. R., Weiss, R. A., Beverley, P. C., Montagnier, L., Alhalabi, M. F., Gluckmann, J. C., and Klatzmann, D. (1988) The human and simian immunodeficiency viruses HIV-1, HIV-2 and SIV interact with similar epitopes on their cellular receptor, the CD4 molecule. AIDS 2, Clapham, P. R., Blanc, D., and Weiss, R. A. (1991) Specific cell surface requirements for the infection of CD4-positive cells by human immunodeficiency virus types 1 and 2 and by Simian immunodeficiency virus. Virology 181, Alkhatib, G., Combadiere, C., Broder, C. C., Feng, Y., Kennedy, P. E., Murphy, P. M., and Berger, E. A. (1996) CC CKR5: a RANTES, MIP- 1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV- 1. Science 272, Feng, Y., Broder, C. C., Kennedy, P. E., and Berger, E. A. (1996) HIV-1 entry cofactor: functional cdna cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, Berger, E. A., Murphy, P. M., and Farber, J. M. (1999) Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. 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5 CELL SURFACE RECEPTORS Kwong, P. D., Wyatt, R., Robinson, J., Sweet, R. W., Sodroski, J., and Hendrickson, W. A. (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, Geijtenbeek, T. B., Kwon, D. S., Torensma, R., van Vliet, S. J., van Duijnhoven, G. C., Middel, J., Cornelissen, I. L., Nottet, H. S., KewalRamani, V. N., Littman, D. R., Figdor, C. G., and van Kooyk, Y. (2000) DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, Sullivan, N. J. (2001) Antibody-mediated enhancement of viral disease. Curr. Top. Microbiol. Immunol. 260, McClure, M. O., Marsh, M., and Weiss, R. A. (1988) Human immunodeficiency virus infection of CD4-bearing cells occurs by a ph-independent mechanism. EMBO J. 7, McClure, M. O., Sommerfelt, M. A., Marsh, M., and Weiss, R. A. (1990) The ph independence of mammalian retrovirus infection. J. Gen. Virol. 71, McKnight, A., Griffiths, D. J., Dittmar, M., Clapham, P., and Thomas, E. (2001) Characterization of a late entry event in the replication cycle of human immunodeficiency virus type 2. J. Virol. 75, O Brien, S. J., and Moore, J. P. (2000) The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol. Rev. 177, Simmons, G., Clapham, P. R., Picard, L., Offord, R. E., Rosenkilde, M. M., Schwartz, T. W., Buser, R., Wells, T. N. C., and Proudfoot, A. E. (1997) Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276, Strizki, J. M., Xu, S., Wagner, N. E., Wojcik, L., Liu, J., Hou, Y., Endres, M., Palani, A., Shapiro, S., Clader, J. W., Greenlee, W. J., Tagat, J. R., McCombie, S., Cox, K., Fawzi, A. B., Chou, C. C., Pugliese-Sivo, C., Davies, L., Moreno, M. E., Ho, D. D., Trkola, A., Stoddart, C. A., Moore, J. P., Reyes, G. R., and Baroudy, B. M. (2001) SCH-C (SCH ), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 98, Smith, D. H., Byrn, R. A., Marsters, S. A., Gregory, T., Groopman, J. E., and Capon, D. J. (1987) Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen. Science 238, Clapham, P. R., Weber, J. N., Whitby, D., McIntosh, K., Dalgleish, A. G., Maddon, P. J., Deen, K. C., Sweet, R. W., and Weiss, R. A. (1989) Soluble CD4 blocks the infectivity of diverse strains of HIV and SIV for T cells and monocytes but not for brain and muscle cells. Nature 337, Daar, E. S., Li, X. L., Moudgil, T., and Ho, D. D. (1990) High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. Proc. Natl. Acad. Sci. U.S.A. 87, Mothes, W., Boerger, A. L., Narayan, S., Cunningham, J. M., and Young, J. A. (2000) Retroviral entry mediated by receptor priming and low ph triggering of an envelope glycoprotein. Cell 103, Weiss, R. A. (1993) Cellular receptors and viral glycoproteins involved in retrovirus entry. In: The Retroviridae (Levy, J. A., ed.). Vol 2: pp , Plenum Press, New York.

Fayth K. Yoshimura, Ph.D. September 7, of 7 HIV - BASIC PROPERTIES

Fayth K. Yoshimura, Ph.D. September 7, of 7 HIV - BASIC PROPERTIES 1 of 7 I. Viral Origin. A. Retrovirus - animal lentiviruses. HIV - BASIC PROPERTIES 1. HIV is a member of the Retrovirus family and more specifically it is a member of the Lentivirus genus of this family.